Two new projects using drugs as pharmacological tools to test the hypothesis of reversible synaptic failure in the early course of dementia of the Alzheimer's type (DAT) were approved by the NIA- IRB. Idazoxan is used to modulate noradrenergic synaptic norepinephrine concentration and physostigmine for cholinergic system. In addition to using pharmacological agents to modulate the neurotransmitter system, we also use cognitive tasks of varying difficulty (parametric stimulation) to potentiate the drug efficacy. A new therapeutic trial using tetrahydrobiopterin to treat DAT was also approved by the IRB. This therapeutic trial is based on our previous work, which showed that biopterine and monoamines are reduced in DAT patients with extrapyramidal signs. We propose that biopterine and monoamine deficiency contributes to the progression of DAT, which can be halted with the supplement of tetrahydrobiopterin. In addition to the three new projects, we have important findings in the pharmacokinetics and pharmacodynamics of arecoline and physostigmine. The verbal memory was improved with arecoline administration in a majority of patients with mild-moderate Alzheimer's disease. The dose response of arecoline on different cognitive modalities showed that verbal ability tended to improve at low doses of arecoline, whereas attention and visuospatial ability tended to improve at higher doses. The mechanism of arecoline-induced memory improvement is not due to induction of stress nor to elevation peripheral corticosteroid levels. Most DAT patients (5/9) responded to chronic intravenous infusion of physostigmine and showed a significant, reproducible but modest improvement in verbal memory. Further, the memory enhancement was significantly correlated with butyrylcholinesterase inhibition but not with plasma physostigmine concentration.